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Multi-photon Imaging of Tumor Cell Invasion in an Orthotopic Mouse Model of Oral Squamous Cell Carcinoma
Published on: July 25, 2011
Aberrantly hypermethylated tumor suppressor genes were identified in oral squamous cell carcinoma (OSCC)
Soo Yeon Kim1, Yu Kyeong Han2, Jae Min Song3,4
1Department of Oral Pathology, School of Dentistry, Pusan National University, Yangsan, 50612, Gyeongsangnam-do, Republic of Korea.
Background:
Oral squamous cell carcinoma (OSCC) is a genetic and epigenetic disease. There is growing evidence to suggest that environmental factors due to epigenetic changes can be involved in the OSCC pathogenesis. Although tumor suppressor genes (TSGs) are commonly inactivated by promoter hypermethylation in human cancers, the epigenetic changes and the mechanism of TSGs in human OSCC remain unclear. We therefore assessed the methylation status of the TSGs, which are associated with epigenetic silencing in human cancers, OSCC cell lines, primary tumors, and normal oral mucosa.
Results:
We used 14 TSGs that were originally identified in colon cancer to investigate the aberrant hypermethylation of these genes associated with transcriptional silencing in 10 OSCC cell lines. We found three TSGs, TFPI2, SOX17, and GATA4, that are robustly hypermethylated and are associated with transcriptional silencing in OSCC cell lines. The re-expression of the three genes was induced by 5-aza-2'-deoxycytidine (5-aza-dC) in cells in which these genes were not expressed or had a lack of expression. In 33 cases of primary OSCC tumors, promoter hypermethylation was detected for the TFPI2, SOX17, and GATA4 genes at (32/33) 97%, (22/33) 67%, and (11/33) 33%, respectively. Eleven normal oral mucosa samples showed no promoter hypermethylation for all three genes, which suggests that this promoter hypermethylation is cancer-specific. Bisulfite sequencing analysis confirmed the cancer-specific methylation of the TFPI2, SOX17, and GATA4 promoters in the OSCC cell lines and tumors but not in the normal oral mucosa samples. More importantly, the methylation status of TFPI2, GATA4, and SOX17 was significantly associated with OSCC patients' overall survival through TCGA DNA methylation database.
Conclusions:
We identified that TFPI2, SOX17, and GATA4 are frequently hypermethylated in human OSCC cells in a cancer-specific manner and that the transcriptional expression of these genes is regulated by promoter hypermethylation in OSCC. Our results highlight the great potential used as a synergistic biomarker set to improve the prognosis and therapeutic treatment for patients with OSCC.
Insights
Hypermethylation of TFPI2, SOX17, and GATA4 genes is common in oral squamous cell carcinoma (OSCC) and linked to patient survival. These genes show potential as biomarkers for improved OSCC prognosis and treatment.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Oral squamous cell carcinoma (OSCC) is a complex disease influenced by genetic and epigenetic factors.
- Environmental factors may contribute to OSCC pathogenesis through epigenetic modifications.
- The role of tumor suppressor genes (TSGs) and their epigenetic silencing in OSCC remains incompletely understood.
Purpose of the Study:
- To investigate the promoter methylation status of specific TSGs in OSCC.
- To determine if TSG hypermethylation is associated with transcriptional silencing in OSCC.
- To evaluate the potential of these TSGs as biomarkers for OSCC prognosis.
Main Methods:
- Assessed methylation status of 14 TSGs in OSCC cell lines, primary tumors, and normal oral mucosa.
- Utilized 5-aza-2'-deoxycytidine (5-aza-dC) to assess gene re-expression.
- Confirmed methylation patterns using bisulfite sequencing and analyzed survival associations via TCGA database.
Main Results:
- TFPI2, SOX17, and GATA4 were found to be frequently hypermethylated and transcriptionally silenced in OSCC cell lines.
- Promoter hypermethylation of TFPI2, SOX17, and GATA4 was detected in 97%, 67%, and 33% of primary OSCC tumors, respectively.
- This hypermethylation was cancer-specific, absent in normal oral mucosa, and significantly correlated with OSCC patient survival.
Conclusions:
- TFPI2, SOX17, and GATA4 are frequently hypermethylated in OSCC in a cancer-specific manner.
- Promoter hypermethylation regulates the transcriptional expression of these TSGs in OSCC.
- These genes represent a promising synergistic biomarker set for improving OSCC prognosis and therapeutic strategies.
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